The US Surgeon General has reported that diseases of the craniofacial region are among the most common health problems affecting the general population. Among these maladies, devastating head and neck cancers (HNC) single-handedly impose a significant biomedical burden by accounting for 8000 deaths and over 40,000 new cases each year in the U.S. alone. Most of these patients will require multimodality treatment with surgery, radiation, and chemotherapy. Although radiotherapy has increased survival it also results in damage to adjacent normal tissues leading to significant morbidity. The corrosive impact of these radiation induced side effects can be unrelenting and their complex management is rarely remedial. Surgical treatment of HNC poses an ongoing challenge as it is complicated by the severely problematic wound healing issues consequent to adjuvant radiation therapy. Standard of care currently dictates mandibular reconstruction utilizing free tissue transfer, requiring the harvest of bone and tissue from other parts of the body (leg, rib, or arm). These large, involved, and complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of radiation and/or chemotherapy jeopardizing prognosis as well as quality of life. Advances in biotechnology and surgical instrumentation have afforded a unique opportunity for collaborative efforts combining knowledge from both basic and clinical investigation to conduct translational research. This translational research has the potential to transform head and neck cancer reconstruction by bringing novel and more effective therapeutic strategies into clinical settings. The utilization of Distraction Osteogenesis (DO) for tissue replacement after oncologic resection or as a reconstructive option for deformations secondary to irradiated bone could have immense potential therapeutic ramifications. DO, the creation of new bone by the gradual separation of two osteogenic fronts, generates an anatomical and functional replacement of deficient tissue from local substrate. Radiation drastically impairs bone healing, precluding the utilization of DO as a durable and predictable reconstructive method for HNC. The central hypothesis to be tested in this proposal is that the deleterious effects of radiation on bone formation can be mitigated to allow functional restoration and successful regeneration of the mandible. To test this hypothesis we will utilize a novel rodent model of DO to generate specific metrics of diminished bone quality within the regenerate of irradiated distracted mandibles. We will then employ a series of pharmacologic and tissue engineering strategies to assuage the adverse impact of radiation induced injury on new bone formation and healing in order to optimize reconstruction and repair. The long term goal of this proposal is to provide fundamental information that can be translated from the bench to the bedside to lead to improved treatment modalities to this severely compromised patient population. [unreadable] [unreadable] [unreadable]